KEGG   PATHWAY: hsa05231
hsa05231                    Pathway                                
Choline metabolism in cancer - Homo sapiens (human)
Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, oncogenic signalling via pathways such as the RAS and PI3K-AKT pathways, and transcription factors associated with oncogenesis such as hypoxia-inducible factor 1 (HIF1) mediate overexpression and activation of choline cycle enzymes, which causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These products of choline phospholipid metabolism, such as phosphocholine (PCho), diacylglycerol (DAG) and phosphatidic acid, may function as second messengers that are essential for the mitogenic activity of growth factors, particularly in the activation of the ras-raf-1-MAPK cascade and protein kinase C pathway.
Human Diseases; Cancer: overview
Pathway map
hsa05231  Choline metabolism in cancer

Homo sapiens (human) [GN:hsa]
1950  EGF; epidermal growth factor [KO:K04357]
5154  PDGFA; platelet derived growth factor subunit A [KO:K04359]
5155  PDGFB; platelet derived growth factor subunit B [KO:K17386]
56034  PDGFC; platelet derived growth factor C [KO:K05450]
80310  PDGFD; platelet derived growth factor D [KO:K05450]
1956  EGFR; epidermal growth factor receptor [KO:K04361] [EC:]
5156  PDGFRA; platelet derived growth factor receptor alpha [KO:K04363] [EC:]
5159  PDGFRB; platelet derived growth factor receptor beta [KO:K05089] [EC:]
2885  GRB2; growth factor receptor bound protein 2 [KO:K04364]
6654  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
5900  RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:]
123745  PLA2G4E; phospholipase A2 group IVE [KO:K16342] [EC:]
5321  PLA2G4A; phospholipase A2 group IVA [KO:K16342] [EC:]
8681  JMJD7-PLA2G4B; JMJD7-PLA2G4B readthrough [KO:K16342] [EC:]
100137049  PLA2G4B; phospholipase A2 group IVB [KO:K16342] [EC:]
8605  PLA2G4C; phospholipase A2 group IVC [KO:K16342] [EC:]
283748  PLA2G4D; phospholipase A2 group IVD [KO:K16342] [EC:]
255189  PLA2G4F; phospholipase A2 group IVF [KO:K16342] [EC:]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
5170  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:]
7248  TSC1; TSC complex subunit 1 [KO:K07206]
7249  TSC2; TSC complex subunit 2 [KO:K07207]
6009  RHEB; Ras homolog, mTORC1 binding [KO:K07208]
2475  MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:]
6198  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:]
6199  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:]
1978  EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
23396  PIP5K1C; phosphatidylinositol-4-phosphate 5-kinase type 1 gamma [KO:K00889] [EC:]
8394  PIP5K1A; phosphatidylinositol-4-phosphate 5-kinase type 1 alpha [KO:K00889] [EC:]
8395  PIP5K1B; phosphatidylinositol-4-phosphate 5-kinase type 1 beta [KO:K00889] [EC:]
7454  WAS; WASP actin nucleation promoting factor [KO:K05747]
5879  RAC1; Rac family small GTPase 1 [KO:K04392]
5880  RAC2; Rac family small GTPase 2 [KO:K07860]
5881  RAC3; Rac family small GTPase 3 [KO:K07861]
8936  WASF1; WASP family member 1 [KO:K05753]
10163  WASF2; WASP family member 2 [KO:K05748]
10810  WASF3; WASP family member 3 [KO:K06083]
6667  SP1; Sp1 transcription factor [KO:K04684]
5337  PLD1; phospholipase D1 [KO:K01115] [EC:]
5338  PLD2; phospholipase D2 [KO:K01115] [EC:]
60482  SLC5A7; solute carrier family 5 member 7 [KO:K14387]
23446  SLC44A1; solute carrier family 44 member 1 [KO:K06515]
80736  SLC44A4; solute carrier family 44 member 4 [KO:K15377]
204962  SLC44A5; solute carrier family 44 member 5 [KO:K15377]
57153  SLC44A2; solute carrier family 44 member 2 [KO:K15377]
126969  SLC44A3; solute carrier family 44 member 3 [KO:K15282]
6580  SLC22A1; solute carrier family 22 member 1 [KO:K08198]
6582  SLC22A2; solute carrier family 22 member 2 [KO:K08199]
6581  SLC22A3; solute carrier family 22 member 3 [KO:K08200]
6584  SLC22A5; solute carrier family 22 member 5 [KO:K08202]
6583  SLC22A4; solute carrier family 22 member 4 [KO:K08202]
1119  CHKA; choline kinase alpha [KO:K14156] [EC:]
1120  CHKB; choline kinase beta [KO:K14156] [EC:]
3091  HIF1A; hypoxia inducible factor 1 subunit alpha [KO:K08268]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
9468  PCYT1B; phosphate cytidylyltransferase 1B, choline [KO:K00968] [EC:]
5130  PCYT1A; phosphate cytidylyltransferase 1A, choline [KO:K00968] [EC:]
56994  CHPT1; choline phosphotransferase 1 [KO:K00994] [EC:]
5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:]
8611  PLPP1; phospholipid phosphatase 1 [KO:K01080] [EC:]
8613  PLPP3; phospholipid phosphatase 3 [KO:K01080] [EC:]
8612  PLPP2; phospholipid phosphatase 2 [KO:K01080] [EC:]
8525  DGKZ; diacylglycerol kinase zeta [KO:K00901] [EC:]
8527  DGKD; diacylglycerol kinase delta [KO:K00901] [EC:]
9162  DGKI; diacylglycerol kinase iota [KO:K00901] [EC:]
1606  DGKA; diacylglycerol kinase alpha [KO:K00901] [EC:]
8526  DGKE; diacylglycerol kinase epsilon [KO:K00901] [EC:]
1607  DGKB; diacylglycerol kinase beta [KO:K00901] [EC:]
160851  DGKH; diacylglycerol kinase eta [KO:K00901] [EC:]
1608  DGKG; diacylglycerol kinase gamma [KO:K00901] [EC:]
1609  DGKQ; diacylglycerol kinase theta [KO:K00901] [EC:]
139189  DGKK; diacylglycerol kinase kappa [KO:K00901] [EC:]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:]
5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:]
10434  LYPLA1; lysophospholipase 1 [KO:K06128] [EC:]
56261  GPCPD1; glycerophosphocholine phosphodiesterase 1 [KO:K18695] [EC:]
C00093  sn-Glycerol 3-phosphate
C00114  Choline
C00157  Phosphatidylcholine
C00162  Fatty acid
C00165  Diacylglycerol
C00307  CDP-choline
C00416  Phosphatidate
C00588  Choline phosphate
C00670  sn-Glycero-3-phosphocholine
C04230  1-Acyl-sn-glycero-3-phosphocholine
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Glunde K, Bhujwalla ZM, Ronen SM
Choline metabolism in malignant transformation.
Nat Rev Cancer 11:835-48 (2011)
Beloueche-Babari M, Chung YL, Al-Saffar NM, Falck-Miniotis M, Leach MO
Metabolic assessment of the action of targeted cancer therapeutics using magnetic resonance spectroscopy.
Br J Cancer 102:1-7 (2010)
Abalsamo L, Spadaro F, Bozzuto G, Paris L, Cecchetti S, Lugini L, Iorio E, Molinari A, Ramoni C, Podo F
Inhibition of phosphatidylcholine-specific phospholipase C results in loss of mesenchymal traits in metastatic breast cancer cells.
Breast Cancer Res 14:R50 (2012)
Foster DA
Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells.
Biochim Biophys Acta 1791:949-55 (2009)
Beloueche-Babari M, Jackson LE, Al-Saffar NM, Eccles SA, Raynaud FI, Workman P, Leach MO, Ronen SM
Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells.
Mol Cancer Ther 5:187-96 (2006)
Ridgway ND
The role of phosphatidylcholine and choline metabolites to cell proliferation and survival.
Crit Rev Biochem Mol Biol 48:20-38 (2013)
Awwad HM, Geisel J, Obeid R
The role of choline in prostate cancer.
Clin Biochem 45:1548-53 (2012)
Iorio E, Mezzanzanica D, Alberti P, Spadaro F, Ramoni C, D'Ascenzo S, Millimaggi D, Pavan A, Dolo V, Canevari S, Podo F
Alterations of choline phospholipid metabolism in ovarian tumor progression.
Cancer Res 65:9369-76 (2005)
Ackerstaff E, Glunde K, Bhujwalla ZM
Choline phospholipid metabolism: a target in cancer cells?
J Cell Biochem 90:525-33 (2003)
Park JB, Lee CS, Jang JH, Ghim J, Kim YJ, You S, Hwang D, Suh PG, Ryu SH
Phospholipase signalling networks in cancer.
Nat Rev Cancer 12:782-92 (2012)
Yalcin A, Clem B, Makoni S, Clem A, Nelson K, Thornburg J, Siow D, Lane AN, Brock SE, Goswami U, Eaton JW, Telang S, Chesney J
Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling.
Oncogene 29:139-49 (2010)
Glunde K, Jiang L, Moestue SA, Gribbestad IS
MRS and MRSI guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer.
NMR Biomed 24:673-90 (2011)
Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, Thomas AL, Armstrong MD, Arteaga CL, Lindsley CW, Brown HA
Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.
Nat Chem Biol 5:108-17 (2009)
Foster DA, Xu L
Phospholipase D in cell proliferation and cancer.
Mol Cancer Res 1:789-800 (2003)
Zhou H, Huang S
mTOR signaling in cancer cell motility and tumor metastasis.
Crit Rev Eukaryot Gene Expr 20:1-16 (2010)
hsa00564  Glycerophospholipid metabolism
hsa04010  MAPK signaling pathway
hsa04150  mTOR signaling pathway
hsa04151  PI3K-Akt signaling pathway
hsa04810  Regulation of actin cytoskeleton
KO pathway

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